Fluoro-prostaglandins and process for their preparation

ABSTRACT

Fluoro-prostaglandin compounds are disclosed, such as, for instance, 18,19,20-trinor-17-cyclohexyl-13-14-dehydro-16(S,R)-fluoro-PGF 2 .alpha.. 
     The fluoro-prostaglandins of the present invention have the same therapeutical uses as natural prostaglandins, but have the advantage of being resistant to the enzyme 15-prostaglandin dehydrogenase, and also exhibit a more selective therapeutical action. Certain of the compounds of the present invention exhibit very favorable luteolytic and antiulcer activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation of our copending application Ser. No. 833,999,filed Sept. 16, 1977, which in turn is a divisional of application Ser.No. 779,632, filed Mar. 21, 1977, which was a continuation ofapplication Ser. No. 667,261 filed Mar. 15, 1976 all of which are nowabandoned.

The present invention relates to fluoro-prostaglandins, a process fortheir preparation, and pharmaceutical compositions containing them.

The compounds of the invention are optically active or racemicprostaglandins of formula (I) ##STR1## wherein

R is a member selected from the group consisting of hydrogen, a C₁ -C₁₂alkyl group and a cation of a pharmaceutically acceptable base;

the symbol represents a single or a double bond, wherein, when thesymbol is a double bond, R₃ is a hydrogen atom and R₁ and R₂ togetherform an oxo group, while, when the symbol is a single bond, R₃ ishydroxy, and one of R₁ and R₂ is hydrogen and the other is hydroxy oracyloxy or R₁ and R₂, taken together, form an oxo group;

A is trans --CH═CH-- or --C.tbd.C--; one of R₄ and R₅ is hydroxy and theother is hydrogen;

R₆ is a member selected from the group consisting of hydrogen, methyland fluorine;

n is zero, or an integer of 1 to 6;

R₇, when A is trans --CH═CH--, is a cycloalkyl group containing 3 to 7ring carbon atoms, while, when A is --C.tbd.C--, R₇ is a member selectedfrom the group consisting of methyl, cycloalkyl containing 3 to 7 ringcarbon atoms and phenyl unsubstituted or optionally substituted by oneor more substituents selected from the group consisting of halogen, C₁-C₆ alkoxy and trihalomethyl.

The double bond in the 5(6)-position is a cis-double bond.

In the formulae of this specification, the broken lines ( ) indicatethat the substituents are in the α-configuration, i.e. are below theplane of the ring or of the chain, while the heavy solid lines ( )indicate that the substituents are in the β-configuration, i.e. abovethe plane of the ring or of the chain; the wavy line attachment ( )indicates that the groups may be either in the α-configuration, i.e.below the plane of the ring or of the chain, or in the β-configuration,i.e. above the plane of the ring or of the chain.

As is evident from formula (I), the hydroxy group linked to the carbonatom in the 15 position may be either in the α-configuration ##STR2## orin the β-configuration ##STR3## When on the carbon atom in the16-position there is only one fluorine atom, said substituent may beeither a 16S-fluoro (α-configuration) or a 16R-fluoro (β-configuration)or a 16(S,R)-fluoro, i.e. the mixture of the two 16S- and 16R-diastereoisomers. Analogously, when on the carbon atom in 16-position,there is a methyl group, said substituent may be either a 16S-methyl ora 16R-methyl or a 16(S,R)-methyl.

It is also evident that when the symbol represents a double bond andtherefore R₃ is a hydrogen atom, this hydrogen atom, being linked to acarbon atom which is no more asymmetric, may be obviously in an only onefixed position, i.e. on the plane of the ring, and therefore it may beneither in the α-position (i.e. below the plane of the ring) nor in theβ-position (i.e. above the plane of the ring).

The alkyl and alkoxy groups may be branched or straight chain groups.

When R is a C₁ -C₁₂ alkyl group, it is preferably a methyl, ethyl,propyl or heptyl group. Preferably, one of R₁ and R₂ is hydrogen and theother is hydroxy or R₁ and R₂, taken together, form an oxo group.

When one of R₁ and R₂ is acyloxy, it is preferably an alkanoyloxy groupcontaining up to 6 carbon atoms, a benzoyloxy or a p-phenylbenzoyloxygroup. When R₇ is methyl, n is preferably 3 or 4; when R₇ is cycloalkylor phenyl, n is preferably 1. When R₇ is a cycloalkyl group, it ispreferably cyclopentyl, cyclohexyl or cycloheptyl.

When R₇ is a trihalomethyl-substituted phenyl, the trihalomethyl groupis preferably trifluoromethyl or trichloromethyl. Examples of cations ofpharmaceutically acceptable bases are either metallic cations, such assodium, potassium, calcium and aluminium or organic amine cations, suchas trialkylamines.

Specific examples of compounds of the invention are the following:

18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-PGF₂α,

18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-PGE₂,

18,19,20-trinor-17-cyclohexyl-16S-fluoro-PGF₂α,

18,19,20-trinor-17-cyclohexyl-16R-fluoro-PGF₂α,

a 16-fluoro-18,19,20-trinor-17-cyclopentyl-PGF₂α,

a 16-fluoro-18,19,20-trinor-17-cyclopentyl-PGE₂,

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGF₂α,

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-PGF₂α,

a 16-fluoro-13,14-dehydro-PGF₂α,

a 16-fluoro-13,14-dehydro-PGE₂,

a 16-fluoro-13,14-dehydro-PGA₂,

a 16-fluoro-13,14-dehydro-PGF₂β,

16S-methyl-16R-fluoro-13,14-dehydro-PGE₂,

16R-methyl-16S-fluoro-13,14-dehydro-PGE₂,

16S,20-dimethyl-16R-fluoro-13,14-dehydro-PGE₂,

16R,20-dimethyl-16S-fluoro-13,14-dehydro-PGE₂,

a 16-methyl,16-fluoro-13,14-dehydro-PGF₂α,

a 16-methyl,16-fluoro-13,14-dehydro-PGF₂β,

a 16-methyl,16-fluoro-13,14-dehydro-PGA₂,

16,16-difluoro-13,14-dehydro-PGE₂,

16,16-difluoro-13,14-dehydro-PGF₂α,

16,16-difluoro-13,14-dehydro-PGA₂,

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-13,14-dehydro-PGF₂α

18,19,20-trinor-17-cyclohexyl-16R-fluoro-13,14-dehydro-PGF₂α,

18,19,20-trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGF₂α,

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGF₂α

a 16-fluoro-18,19,20-trinor-17-cyclopentyl-13,14-dehydro-PGF₂α,

a 16-fluoro-18,19,20-trinor-17-phenyl-13,14-dehydro-PGF₂α,

a 16-fluoro-18,19,20-trinor-17-cyclopentyl-13,14-dehydro-PGE₂,

a 16-fluoro-18,19,20-trinor-17-cyclohexyl-13,14-dehydro-PGE₂,

a 16-fluoro-18,19,20-trinor-17-phenyl-13,14-dehydro-PGE₂,

18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGF₂α,

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGF₂.alpha.,

18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGE₂,

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGE₂,

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGE₂,

The compounds of formula (I) are prepared by a process comprisingreacting an optically active compound, or a racemic mixture of compoundsof formula (II) ##STR4## wherein

n, R₆ and R₇ are as defined above, A' is --C.tbd.C-- or --CH═CX--,wherein X is hydrogen or halogen, Y is hydroxy or a known protectinggroup bound to the ring by an ethereal oxygen atom, and one of R'₄ andR'₅ is hydroxy or a known protecting group bound to the chain by anethereal oxygen atom, and the other is a hydrogen atom, with a Wittigreagent comprising the group of formula --(CH₂)₄ --COOR, wherein R is ahydrogen atom or a C₁ -C₁₂ alkyl group, to give a compound of formula(III) ##STR5## wherein

R, Y, A, R'₄, R'₅, R₆, R₇ and n are as defined above, which when Y is aknown protecting group as above defined, and one of R'₄ and R'₅ is aknown protecting group as above defined and the other is hydrogen, maybe optionally esterified to give the 9α- or 9β-acyloxy derivative, andthen, deetherifying the compound of formula (III) wherein Y is a knownprotecting group as defined above and/or one of R'₄ and R'₅ is a knownprotecting group as defined above and the other is hydrogen, ordeetherifying the 9α- or 9β-acyloxy derivative of the compound offormula (III), so obtaining a compound of formula (I), wherein R₃ is ahydroxy group, the symbol is a single bond, one of R₁ and R₂ ishydrogen, and the other is hydroxy or acyloxy, and one of R₄ and R₅ is ahydroxy group and the other is hydrogen, or, if desired, oxidizing the9α- or 9β-hydroxy group in a compound of formula (IIIa) ##STR6## wherein

R, A, R₆, R₇ and n are as defined above, one of R'₁ and R'₂ is hydrogenand the other is hydroxy, Y' is a known protecting group as definedabove and one of R"₄ and R"₅ is a known protecting group as definedabove and the other is hydrogen, to give a compound of formula (IV)##STR7## wherein

R, Y', A, R"₄, R"₅, R₆, R₇ and n are as defined above, which in turn isdeetherified in the 11- and 15- positions to give, according to thereaction conditions used, either a compound of formula (I) wherein thesymbol is a single bond, R₃ is hydroxy, and R₁ and R₂, taken together,form an oxo group, or a compound of formula (I) wherein the symbol is adouble bond, R₃ is hydrogen, and R₁ and R₂ together form an oxo group,and/or, if desired, reacting a compound of formula (I) wherein R is ahydrogen atom and the hydroxy group in the 11- and/or 15- position isoptionally protected as described above, with a base, followed, ifrequired, by deetherification, to give a compound of formula (I) whereinR is a cation, or esterifying a compound of formula (I) wherein R is ahydrogen atom and the hydroxy group in the 11- and/or 15- position isoptionally protected as described above, followed, if required, bydeetherification, to give a compound of formula (I) wherein R is C₁ -C₁₂alkyl, or hydrolyzing a compound of formula (I) wherein R is C₁ -C₁₂alkyl and the hydroxy group in the 11- and/or 15- position is optionallyprotected as described above, followed, if required, by deetherificationto give a compound of formula (I) wherein R is a hydrogen atom. Thehydrolysis of a compound of formula (I) wherein R₁ and R₂ together forman oxo group and R is C₁ -C₁₂ alkyl group, to give a compound of formula(I) wherein R₁ and R₂ together form an oxo group and R is hydrogen maybe also carried out by enzymatic way, e.g. by using a yeast esterase.

The known protecting groups (i.e. ether groups) should be convertible tohydroxy groups under mild reaction conditions, e.g. acid hydrolysis.Examples are acetalic ethers, enolethers and sylylethers. The preferredgroups are: ##STR8## wherein W is --O-- or --CH₂ --, and Alk is a loweralkyl group.

When in the lactol of formula (II) A'is --CH═CH--, it is a trans--CH═CH--. When in the lactol of formula (II) A' is --CH═CX--, wherein Xis halogen, preferably chlorine, bromine or iodine, the hydrogen atomlinked to the carbon atom in the 13- position and the hydrogen atomlinked to the carbon atom in the 14- position, may be either in thetrans-position (geometric trans-isomers) or in the cis-position(geometric cis-isomers). Preferably, they are in the trans-position.When in the lactol of formula (II) A' is trans --CH═CH--, compounds offormula (III) wherein A is trans --CH═CH-- are obtained; in this case,the Wittig reaction may be performed by using about 2-3 moles of Wittigreagent per mole of lactol and the reaction lasts about one hour.

When in the lactol of formula (II) A' is --C.tbd.C-- or --CH═CX--wherein X is halogen, compounds of formula (III) wherein A is--C.tbd.C-- are obtained.

When A' is --C.tbd.C-- or --CH═CX-- wherein X is bromine or iodine, theWittig reaction may be performed by using about two moles of Wittigreagent per mole of lactol and it is sufficient that the reaction lasts10-20 minutes. When A' is --CH═CX-- wherein X is chlorine, it isnecessary, by using for example 1.5 to 2.5 moles of Wittig reagent permole of lactol, to prolong the reaction time up to 10 hours or, if it isdesired to use shorter reaction times, it is necessary to employ a greatexcess of Wittig reagent (at least 5 moles of Wittig reagent per mole oflactol for reaction time of about 30 minutes).

The Wittig reaction is performed by using the conditions generallyfollowed for this kind of reaction, i.e. in an organic solvent, forexample diethylether, hexane, dimethyl sulphoxide, tetrahydrofuran,dimethylformamide or hexamethylphosphoramide, in the presence of a base,preferably sodium hydride and potassium tert. butoxide, at 0° C. to thereflux temperature of the reaction mixture, preferably at roomtemperature or below.

The term "Wittig reagent" includes compounds of formula ##STR9## whereinR_(a) is aryl or alkyl, Hal is bromine or chlorine and R is hydrogen oralkyl. When R_(a) is alkyl, it is preferably ethyl. The preparation ofthe Wittig reagent is discussed in detail by Tripett, Quart. Rev., 1963,XVII, No. 4, 406.

When in the lactol of formula (II) A' is --CH═CX--, wherein X isbromine, chlorine or iodine, during the reaction with the Wittigreagent, the dehydrohalogenation takes place as easily when the hydrogenatom linked to the carbon atom in the 13- position and the halogen atomlinked to the carbon atom in the 14- position are in the trans-positionas when they are in the cis-position. The optional acylation of the 9α-hydroxy group in the compound of formula (III) may be performed in aconventional manner, for example by treatment with an anhydride or achloride of a carboxylic acid in presence of a base. In this case, a 9α-acyloxy derivative is obtained.

On the contrary, when the acylation of the 9α- hydroxy group in thecompound of formula (III) is carried out with a carboxylic acid inpresence of a compound of formula M^(v) Y₃, wherein M^(v) is a metalloidof the V group and Y is an alkyl, a dialkylamino or an aryl group, andof a hydrogen-acceptor agent, a 9β- acyloxy derivative is obtained, thatis, in the latter case, the esterification involves the completeinversion of configuration of the hydroxy group in the 9- position. Thisreaction is preferably carried out at room temperature in an inertanhydrous solvent, preferably selected from the group consisting ofaromatic hydrocarbons, such as benzene and toluene, linear or cyclicethers, for example diethyl ether, dimethoxyethane, tetrahydrofuran anddioxan. All the used reagents, that are the compounds of formula W^(v)Y₃, the esterifying carboxylic acid and the hydrogen-acceptor agent, areemployed in the proportion of at least 1.5 mole per each mole ofalcohol; 2 to 4 moles of the reagents per each mole of alcohol arepreferably used.

In the compound of formula M^(v) Y₃, M^(v) is preferably P, As, Sb,especially P. Again in the same compound, when Y is alkyl, it ispreferably methyl, while when Y is aryl, it is preferably phenyl; when Yis dialkylamino, it is preferably dimethylamino. The compound of formulaM^(v) Y₃ is preferably selected from the group consisting oftriphenylphosphine, triphenylarsine, triphenylstibine andhexamethyltriaminophosphine of formula [(CH₃)₂ N]₃ P. Thehydrogen-acceptor used is preferably an ester or an amide of theazodicarboxylic acid, preferably ethyl azodicarboxylate, but also otherhydrogen-acceptors may be used, for instance2,3,5,6-tetrachloro-benzoquinone, 2,3-dicyano-5,6-dichlorobenzoquinoneor azobisformamide.

The deetherification reaction of the compound of formula (III)--or ofthe 9α- or 9β-acyloxy derivative of this compound--wherein Y and/or oneof R'₄ and R'₅ are a known protecting group as above defined, isperformed under conditions of mild acid hydrolysis, for example withmono- or poly-carboxylic acids, e.g. formic, acetic, oxalic, citric andtartaric acid, and in a solvent, for example water, acetone,tetrahydrofuran, dimethoxyethane and lower aliphatic alcohols.Preferably, 0.1 to 0.25 N poly-carboxylic acid (e.g. oxalic or citricacid) is used in presence of a convenient low boiling co-solvent whichis miscible with water and which can be easily removed in vacuo at theend of the reaction.

The oxidation of the 9α- or 9β-hydroxy group to yield an oxo group maybe carried out with, for example, Jones reagent or Moffatt reagent.

As stated above, the deetherification of the compound of formula (IV)may give, according to the reaction conditions used, either a compoundof formula (I) wherein the symbol is a single bond, R₃ is hydroxy and R₁and R₂, taken together, form an oxo group, or a compound of formula (I)wherein the symbol is a double bond, R₃ is hydrogen and R₂ and R₃, takentogether, form an oxo group.

The former compound may be obtained as the only product by operating attemperatures ranging between about 25° C. and about 35°-38° C., while byoperating at higher temperatures, for example, at the reflux temperaturefor about three hours, the latter compound is obtained as the onlyproduct.

The lactol of formula (II) may be prepared, in turn, by means of amulti-stop process using as starting material an optically active orracemic lactone of formula (V) ##STR10## wherein

Y" is hydroxy, acyloxy or a known protecting group bound to the ringthrough an ethereal oxygen atom, X, R₆, R₇, and n are as defined above;and wherein the hydrogen atom linked to the carbon atom in the 13-position and the halogen atom linked to the carbon atom in the 14-position (prostaglandin numbering) may be either in the trans-positionor in the cis-position. The multi-step process to prepare the compoundof general formula (II) starting from the lactone of formula (V)involves the following steps:

(a) reduction of the 15-oxo group (prostaglandin numbering) of thelactone of formula (V) to yield a mixture of 15S- and 15R-ols having theformulae (VIa) and (VIb) ##STR11## wherein Y", X, R₆, R₇, and n are asabove defined, followed by the separation of the 15S-ol from the 15R-oland, if desired, by the dehydrohalogenation of the separated alcoholswherein X is halogen to give a compound of formula (VIIa) ##STR12##wherein Y", R₆, R₇, and n are as above defined. If desired, thereduction may follow the dehydrohalogenation. The reduction of the15-oxo group may be suitably performed in an organic solvent, such asacetone, diethylether, dimethoxyethane, dioxan, or benzene or theirmixtures, by using e.g. metal borohydrides, in particular sodiumborohydride, lithium borohydride, zinc borohydride, sodiumtrimethoxyborohydride.

The separation of the 15S-ol from the 15R-ol may be performed bychromatography, e.g. silica gel chromatography or by fractionatedcrystallization. The dehydrohalogenation may be performed in a solvent,preferably selected from the group consisting of dimethylsulphoxide,dimethylformamide, hexamethylphosphoramide in presence of a base whichmay be for example an alkaline metal amide, potassium tert. butylate orthe anion ##STR13##

(b) Conversion of a compound of formula (VIII) ##STR14## wherein

Y", R₆, R₇, A', and n are as defined above and one of R₄ and R₅ is ahydrogen atom and the other is a hydroxy group into a compound offormula (IX) ##STR15## wherein

A', R₆, R₇, and n are as defined above, Y' is a known protecting groupbound to the ring through an ethereal oxygen atom, and one of R"₄ andR"₅ is a known protecting group bound to the chain by an ethereal oxygenatom and the other is a hydrogen atom. The etherification of thecompound of formula (VIII) to give a compound of formula (IX) ispreceded when, in the compound of formula (VIII), Y" is an acyloxygroup, by saponification for example by mild treatment with an alkali,to give a compound of formula (VIII) wherein Y" is a hydroxy group.

The etherification is preferably carried out with a vinylic ether offormula ##STR16## wherein W is --O-- or --CH₂ --, in presence ofcatalytic amounts of, for example, phosphorus oxychloride,p-toluenesulphonic acid or benzene sulphonic acid, or with a silylether, for instance by reacting a trisubstituted chlorosilane inpresence of an acceptor base (for example a trialkylamine) of thehydrogen halide formed, or with an enol ether, for instance by reaction,in presence of an acid catalyst with a 1,1-dialkoxy-cyclopentane orcyclohexane, at the reflux temperature in an inert solvent anddistilling the alcohol formed to obtain mixed dialkoxy ethers or enolethers, according to the quantity of catalyst used or the heating time.

(c) Reduction of the compound of formula (IX) to yield a lactolderivative of formula (X) ##STR17## wherein

Y', A', R"₄, R"₅, R₆, R₇, and n are as above defined. The reduction maybe performed by treatment with diisobutylaluminium hydride or sodiumbis-(2-methoxyethoxy)-aluminium hydride in an inert solvent, forexample, toluene, n-heptane, n-hexane or benzene or their mixtures, atbelow 30° C.

(d) Optional deetherification of the compound of formula (X) to give acomound having the free 11- and 15-hydroxy groups. The deetherificationmay be carried out by mild acid hydrolysis, in a solvent miscible withwater, with a solution of a mono- or poly-carboxylic acid.

All the compounds mentioned under items (a) to (d) may be eitheroptically active compounds or racemic mixtures thereof.

The lactone of formula (V) may be in turn prepared in an only one stepby reaction of an optically active or racemic aldehyde of formula (XI)##STR18## wherein

Y" is as defined above, with an optically active or racemic phosphonatecarbanion of formula (XII) ##STR19##

wherein R_(b) is lower alkyl,

X, R₆, R₇, and n are as defined above. The reaction is suitablyperformed in a solvent which is preferably dry benzene, dimethoxyethane,tetrahydrofuran, dimethylformamide or their mixtures, and using asuspension of 1.1-1.2 molar equivalent of the halo-phosphonatecarbanion.

When in the aldehyde of formula (XI) Y" is an acyloxy group, it may befor example, acetoxy, propionyloxy, benzoyloxy and p-phenyl-benzoyloxy.When Y" is a known protecting group bound to the ring through anethereal oxygen atom, it may be for example one of the etherealprotecting groups reported here-above.

The aldehyde of formula (XI) may be prepared substantially as describedby E. J. Corey et al., Ann. of New York Acad. of Sciences, 180, 24(1971).

The phosphonate carbanion of formula (XII) may be in turn prepared byreacting a phosphonate of formula (XIII) ##STR20## wherein

R_(b), X, R₆, R₇, and n are as defined above, with an equivalent of abase preferably selected from the group consisting of sodium hydride,lithium hydride, calcium hydride, an alkyl lithium derivative and theanion CH₃ --SO₂ --CH₂.sup.(-).

The phosphonate of formula (XIII), wherein X is halogen, may be obtainedby halogenation of a phosphonate of formula (XIV) ##STR21## whereinR_(b), R₆, R₇, and n are as defined above. The halogenation may becarried out in a conventional manner, operating substantially as in thehalogenation of β-ketoesters. The phosphonate of formula (XIV) may beprepared by known methods, e.g. according to E. J. Corey et al., J. Am.Chem. Soc. 90, 3247 (1968) and E. J. Corey and G. K. Kwiatkowsky, J. Am.Chem. Soc., 88, 5654 (1966). Preferably, the phosphonate of formula(XIV) is prepared by reaction of lithium methylphosphonate with a loweralkylester of the optionally substituted aliphatic acid. When thealiphatic acid contains asymmetric carbon atoms, it is possible to useeither the racemic acid or one of its optical antipodes. The lower alkylester of the optionally substituted aliphatic acid may be prepared byconventional methods.

Alternatively, the phosphonate carbanion of formula (XII) wherein X ishalogen may be prepared in situ by reacting a phosphonate carbanion offormula (XII), wherein X is hydrogen, and R_(b), R₆, R₇, and n are asdefined above, with an equivalent of a halogenating agent selected fromthe group consisting of N-chloroacetamide, N-chlorosuccinimide,N-bromosuccinimide, N-bromoacetamide, N-bromocaprolactame,N-iodosuccinimide.

In the preparation of the halo-lactone of formula (V), wherein A' is--CH═CX--, according to the here-above described methods, both compoundswherein the hydrogen atom linked to the carbon atom in the 13-positionand the halogen atom linked to the carbon atom in the 14-position(prostaglandin numbering) are in the trans-position (geometrictrans-isomers) and compounds wherein said atoms are in the cis-position(geometric cis-isomers) are obtained. The geometric trans-isomers areobtained in a far higher percentage (92-95%), while the geometriccis-isomers are obtained in a far lower percentage (5-8%).

The geometric trans-isomers of formula ##STR22## can be easilydistinguished from the geometric cis-isomers of formula ##STR23## inthat the H_(A) vinylic protons of the two isomers resonate at differentpositions and the coupling constants of the H_(A) vinylic proton withthe H_(B) proton are well different (respectively 9 Hz for thetrans-isomer and 10.2 Hz for the cis-isomer).

Anyway, both the trans-isomers and the cis-isomers are intermediates forthe synthesis of the 13,14-dehydro-prostaglandins of the invention.

The lactol of formula (II) wherein A' is --C.tbd.C-- may be alsoprepared by dehydrohalogenation of the lactol of formula (II) wherein A'is ##STR24## wherein X is bromine, chlorine or iodine. Thedehydrohalogenation may be carried out in an aprotic solvent preferablyselected from the group consisting of dimethylsulphoxide,dimethylformamide and hexamethylphosphoramide by treatment with a basepreferably selected from the group consisting of potassiumtert.butylate, an alkali metal amide and the anion CH₃--SO--CH₂.sup.(-).

Among the intermediates described in this specification, the followingare compounds of the invention:

(1) a compound of formula (XV) ##STR25## wherein Z is ##STR26## one ofR₄ '" and R₅ '" is hydrogen and the other is hydroxy or a knownprotecting group bound to the chain by an ethereal oxygen atom or, whenZ is >C═O, R₄ '" and R₅ '", taken together, may also be an oxo group,and wherein Y, A', R₆ R₇ and n are as defined above.

(2) A compound of formula (XVI) ##STR27## wherein

Y is hydroxy or a known protecting group bound to the ring by anethereal oxygen atom, one of R₄ " and R₅ " is a known protecting groupbound to the chain by an ethereal oxygen atom and the other is hydrogen,one of R₁ and R₂ is hydrogen and the other is hydroxy or acyloxy or R₁and R₂, taken together, form an oxo group, and R, R₆, R₇, A, n are asdefined above.

The compounds of formula (I) may be used for the same therapeuticalindications as natural prostaglandins, with respect to which, however,they offer the advantage of being no substrates for the enzyme15-prostaglandin dehydrogenase, which, as is known, quickly inactivatesnatural prostaglandins, and, furthermore, are characterized by a moreselective therapeutical action.

The compounds of formula (I), furthermore, competitively inhibit the useof natural prostaglandins as substrate by the same enzyme.

In particular, the compounds of formula (I), wherein R₂ and R₃ arehydroxy, are provided with an outstanding luteolytic activity, i.e. theyare are useful as abortive agents, as shown by Table I, from which itresults that the presence in C₁₆ of a fluorine atom maintains theluteolytic activity unchanged, and, at the same time, reduces thecontracturing activity in the uterine muscles, so allowing adissociation between the two activities, while the compounds of formula(I), wherein R₁ and R₂, together, form an oxo group, and R₃ is hydroxy,are in particular endowed with remarkable luteolytic and anti-ulceractivities, as shown by Table II, from which it results that thepresence in C₁₆ of a fluorine atom improves the anti-ulcer activity andcauses a good luteolytic activity, while it reduces the capacity tostimulate smooth muscles, such as the ileum of guinea-pigs and theuterus of rats.

                  TABLE I                                                         ______________________________________                                                                  Abortion in Rats*                                                Potency Ratio                                                                              (number of abortions/                               Compounds    Rat Uterus   number of rats)                                     ______________________________________                                        PGF.sub.2α                                                                           1            0/10                                                18,19,20-trinor-17-                                                                        3.22         7/10                                                cyclohexyl-PGF.sub.2α                                                   18,19,20-trinor-17-                                                                        0.33         6/12                                                cyclohexyl-16(S,R)-                                                           fluoro-PGF.sub.2α                                                       18,19,20-trinor-17-                                                                        10.59        10/10                                               cyclohexyl-13,14-                                                             dehydro-PGF.sub.2α                                                      18,19,20-trinor-17-                                                                        3.29         10/10                                               cyclohexyl-13,14-                                                             dehydro-16(S,R)-                                                              fluoro-PGF.sub.2α                                                       ______________________________________                                         *In this and the subsequent antifertility experiments, all the compounds      are administered subcutaneously at a dose of 2 mg/kg b.w. (0.2 ml/100 g       b.w.) to female rats on the 10th day of pregnancy after inspection of the     uterus, and implanted fetuses are counted on the same day. Animals are        killed on the 21st day of pregnancy and the presence of any fetal debris      is counted as no abortion.                                               

                  TABLE II                                                        ______________________________________                                                  Potency Ratio                                                                           Anti-    Number of                                                  of Rats   ulcer    Abortions/                                       Compounds   Ileus   Uterus  activity                                                                             Number of Rats                             ______________________________________                                        PGE.sub.2   1       1       1      0/10                                       18,19,20-trinor-17-                                                                       0.27    0.75    0.40   0/10                                       cyclohexyl-PGE.sub.2                                                          18,19,20-trinor-17-                                                                       0.11    0.55    1.20   10/12                                      cyclohexyl-16(S,R)-                                                           fluoro-PGE.sub.2                                                              ______________________________________                                    

The compounds of formula (I) can be administered orally, parenterally,or by intravenous or intrauterine (extra-amniotic or intra-amniotic)way, by rectal suppositories or by inhalation. For example, they can beadministered by intravenous infusion of a sterile isotonic salinesolution at the rate of 0.01 to 10, preferably 0.05 to 1, μg/kg ofmammal body weight per minute.

The invention therefore also provides a pharmaceutical compositioncomprising a compound of formula (I) and a pharmaceutically acceptablecarrier or diluent.

The compositions may be prepared by conventional methods and can be, forexample, in the form of tablets, capsules, pills, suppositories orbougies, or in liquid form e.g. solutions, suspensions or emulsions.

Examples of substances which can serve as carriers or diluents arewater, gelatin, lactose, starches, magnesium stearate, talc, vegetableoil, benzyl alcohol and cholesterol.

The invention is illustrated by the following examples, where theabbreviations THP, DIOX, DMSO, THF, DMF, DIBA, HMPA, Et₂ O, DME,respectively, refer to tetrahydropyranyl, dioxanyl, dimethylsulphoxide,tetrahydrofuran, dimethylformamide, diisobutylalluminium hydride,hexamethylenephosphoramide, ethyl ether and dimethoxyethane.

EXAMPLE 1

A suspension of 1.220 g of NaH (80% dispersion in mineral oil) in 30 mlof dry DMSO, under nitrogen and with humidity excluded is heated at58°-65° C., until no more hydrogen evolves. After cooling to 4°-8° C.,8.92 g of triphenyl-(4-carboxybutyl)-phosphonium bromide is added andthe mixture is stirred until it is all dissolved, with formation of adark red solution of the ylide, maintaining the temperature at about10°-12° C. by means of outside cooling. To this is added a solution in 5ml of anhydrous DMSO of 1.2 g of2-[3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl)-ethanal-γ-lactol.The mixture is stirred for 4 hours, then diluted with 30 ml of water andextracted repeatedly (16 times with 5 ml each) with ethyl ether, toremove the triphenylphosphoxide formed. The combined ether extracts arere-extracted with 0.5 N NaOH (5 times with 5 ml) and then discarded. Thecombined aqueous alkaline extracts are acidified to pH 4.5 with 2 Nsulfuric acid and extracted with ethyl ether-pentane 1:1. These organicextracts are combined, washed to neutral and evaporated to dryness,after drying over Na₂ SO₄, yielding 1.3 g of7-{3α,5α-dihydroxy-(3-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1β-cyclopentyl}-5-cis-heptenoicacid [18,19,20-trinor-17-cyclohexyl,16(R,S)-fluoro-PGF₂α-11,15-bis-THP-ether].

By the same procedure, if one starts with the individual 16S-fluoro and16R-fluoro isomers as well as with one of the following aldehydes:

2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether-4(R,S)-fluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl})-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether)-4,4'-difluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether)-4,4'-difluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;one obtains the following compounds:

18,19,20-trinor-17-cyclohexyl-16S-fluoro-PGF₂α -11,15-bis-THP-ether;

18,19,20-trinor-17-cyclohexyl-16R-fluoro-PGF₂α -11,15-bis-THP-ether;

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-PGF₂α-11,15-bis-THP-ether;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-PGF₂α-11,15-bis-THP-ether;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGF₂α -11,15-bis-THP-ether.

EXAMPLE 2

To a solution of the ylide prepared as described in example 1, startingwith 612 mg of NaH (80% dispersion in mineral oil) and 4.52 g oftriphenyl-(4-carboxybutyl)-phosphonium bromide, in 25 ml of anhydrousDMSO add a solution of 934 mg of2-{3α,5α-dihydroxy-(3-THP-ether)-2β-[2-bromo-(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-trans-1-nonenyl]-1α-cyclopentyl}-ethanal-γ-lactolin 8 ml of DMSO. Keep at room temperature for 10 hours, then dilute with30 ml of water and extract with ether to remove thetriphenylphosphoxide. The combined ether phases are re-extracted with0.5 N NaOH and then discarded. The combined aqueous alkaline phases areacidified to pH 4.5 and extracted with ethyl ether:pentane 1:1. Theseorganic extracts are combined, washed to neutral with saturated aqueousammonium sulfate solution, dried over sodium sulfate and evaporated todryness. The yield is 860 mg of13,14-dehydro-16(R,S)-fluoro-20-methyl-11,15-bis-THP-ether-PGF₂.alpha..

EXAMPLE 3

To a solution of 0.5 g of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂α -11,15-bis-THP-etherin 8 ml of acetone add 10 ml of a 0.25 N aqueous solution of oxalic acidand reflux for 2 hours. Evaporate the excess acetone under vacuum,extract the aqueous phase with ethyl ether. The organic extracts arecombined, washed until neutral with a saturated ammonium sulfatesolution, dried and evaporated to dryness. The residue ischromatographed on acid-washed silica gel and eluted with methylenechloride-ethyl acetate 8:2, yielding 320 mg of pure18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂α ; [α]_(D) ^(EtOH)=+15.1°; [α]₃₆₅°^(EtOH) =+46.8°.

The dioxanyl ethers are deacetalated by the same procedure.

EXAMPLE 4

Add a solution in anhydrous DMSO of 1.75 g of potassium ter-butylate,freshly sublimated, to a solution of 3.46 g oftriphenyl-(4-carboxybutyl)-phosphonium bromide in 25 ml of DMSO,maintaining at about 15° C., under inert gas, and with constantstirring. To the dark red solution of the ylide which is formed add asolution of 770 mg of2-{3α,5α-dihydroxy-(3α-DIOX-ether)-2β-[2-bromo-(3S)-hydroxy-(3-DIOX-ether)-4,4'-difluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactolin 10 ml of a 1:1 mixture of DMSO:THF. Stir for 10 hours, then dilutewith 30 ml of water and extracts the aqueous phase with ethyl ether toremove the triphenylphosphoxide. The ether extracts are re-extractedwith 0.5 N NaOH and then discarded. The aqueous alkaline phases arecombined, acidified to pH 4.5 with 2 N H₂ SO₄ and extracted with ethylether:pentane 1:1. These organic extracts are washed until neutral withsaturated ammonium sulfate solution and evaporated to dryness to give700 mg of 18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGF₂α-11,15-bis-DIOX-ether. Following the procedures of example 2 or example3, starting from the following aldehydes:

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-trans-1-octenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4R-fluoro-4S-methyl-trans-1-octenyl]-1α-cyclopentyl}-ethanal-γ-lactol,and its 4R-methyl-4S-fluoro-isomer;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-trans-1-octenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-trans-1-nonenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4S-fluoro-4R-methyl-trans-1-nonenyl]-1α-cyclopentyl}-ethanal-γ-lactoland its 4S-methyl-4R-fluoro-isomer;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-trans-1-nonenyl]-1α-cyclopentenyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-trans-1-decenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-trans-1-decenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4S-fluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactoland the individual 4S-fluoro and 4R-fluoro isomers;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-4-(4'-fluoro)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-.gamma.-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-4-(3'-chloro)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-.gamma.-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-4-(3'-trifluoromethyl)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol,the following compounds are obtained, either as the 11,15-bis-THP-etheror as the 11,15-bis-DIOX-ethers:

13,14-dehydro-16(R,S)-fluoro-PGF₂α ;

13,14-dehydro-16S-methyl-16R-fluoro-PGF₂α and its16S-fluoro-16R-methyl-isomer;

13,14-dehydro-16,16-difluoro-PGF₂α ;

13,14-dehydro-16,16-difluoro-20-methyl-PGF₂α ;

13,14-dehydro-16S-fluoro-16R,20-dimethyl-PGF₂α and its16R-fluoro-16S-methyl-isomer;

13,14-dehydro-16(R,S)-fluoro-20-methyl-PGF₂α ;

13,14-dehydro-16(R,S)-fluoro-20-ethyl-PGF₂α ;

13,14-dehydro-16,16-difluoro-20-ethyl-PGF₂α ;

18,19,20-trinor-17-cyclopentyl-16S-fluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGF₂.alpha.;

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-13,14-dehydro-PGF₂α and theindividual 16S-fluoro and 16R-fluoro isomers;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-17-phenyl-16(R,S)-fluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-16(R,S)-fluoro-17-(4'-fluoro)-phenyl-13,14-dehydro-PGF.sub.2α;

18,19,20-trinor-16(R,S)-fluoro-17-(3'-chloro)-phenyl-13,14-dehydro-PGF.sub.2α;

18,19,20-trinor-16(R,S)-fluoro-16-(3'-trifluoromethyl)-phenyl-13,14-dehydro-PGF₂α; which are then deacetalated by the procedure described in example 3 togive the following free hydroxy acids:

13,14-dehydro-16(R,S)-fluoro-PGF₂α ;

13,14-dehydro-16S-methyl-16R-fluoro-PGF₂α and its16S-fluoro-16R-methyl-isomer;

13,14-dehydro-16,16-difluoro-PGF₂α ;

13,14-dehydro-16,16-difluoro-20-methyl-PGF₂α ;

13,14-dehydro-16S-fluoro-16R,20-dimethyl-PGF₂α and its16R-fluoro-16S-methyl-isomer;

13,14-dehydro-16(R,S)-fluoro-20-methyl-PGF₂α ;

13,14-dehydro-16(R,S)-fluoro-20-ethyl-PGF₂α ;

13,14-dehydro-16,16-difluoro-20-ethyl-PGF₂α ;

18,19,20-trinor-17-cyclopentyl-16S-fluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGF₂.alpha.;

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-13,14-dehydro-PGF₂α and theindividual 16S-fluoro and 16R-fluoro isomers;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-17-phenyl-16(R,S)-fluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGF₂α ;

18,19,20-trinor-16(R,S)-fluoro-17-(4'-fluoro)-phenyl-13,14-dehydro-PGF.sub.2α;

18,19,20-trinor-16(R,S)-fluoro-17-(3'-chloro)-phenyl-13,14-dehydro-PGF.sub.2α;

18,19,20-trinor-16(R,S)-fluoro-16-(3'-trifluoromethyl)-phenyl-13,14-dehydro-PGF₂α.

EXAMPLE 5

A solution of 0.37 g of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂α -11,15-bis-THP-etherin 10 ml of acetone is cooled to -15° C. and 0.9 ml of Jones reagent isadded. This is maintained at -10° to -12° C. for 30 minutes, thendiluted with 70 ml of benzene, washed repeatedly with saturated aqueousammonium sulfate until neutral (10 times 5 ml). It is then dried oversodium sulfate and evaporated to dryness.

The crude reaction product is dissolved in 60 ml of acetone and combinedwith 80 ml of an aqueous 0.1 N sodium oxalate solution. The mixture ismaintained at 40° C. for 10 hours. The acetone is evaporated undervacuum and the aqueous phase extracted with ether. The combined organicextracts are washed until neutral, dried and evaporated to dryness. Theresidue is chromatographed on acid-washed silica gel and eluted withmethylene chloride-ethyl acetate to give 0.2 g of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGE₂, [α]_(D) =-47.8°,[α]₃₆₅° =-291° (EtOH).

Using the above procedure and starting with compounds prepared asdescribed in examples 1, 2 and 3, in the form of the 11,15-bis-acetals,after oxidation with Jones reagent and subsequent deacetalation thefollowing PGE₂ derivatives are obtained:

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-PGE₂ ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-PGE₂ ;

18,19,20-trinor-17-cyclohexyl-16(R,S)-PGE₂ and the individual 16S and16R isomers;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGE₂ ;

13,14-dehydro-16(R,S)-fluoro-PGE₂ ; [α]_(D) =-3.6° (EtOH);

13,14-dehydro-16S-methyl-16R-fluoro-PGE₂ and its16R-methyl-16S-fluoro-isomer;

13,14-dehydro-16,16-difluoro-PGE₂ ;

13,14-dehydro-16(R,S)-fluoro-20-methyl-PGE₂ ;

13,14-dehydro-16S-fluoro-16R,20--dimethyl-PGE₂ and its16S-methyl-16R-fluoro-isomer;

13,14-dehydro-16,16-difluoro-20-methyl-PGE₂ ;

13,14-dehydro-16(R,S)-fluoro-20-ethyl-PGE₂ ;

13,14-dehydro-16,16-difluoro-20-ethyl-PGE₂ ;

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-13,14-dehydro-PGE₂ ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGE₂ ;

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-13,14-dehydro-PGE₂ and theindividual 16S-fluoro and 16R-fluoro isomers;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGE₂ ;

18,19,20-trinor-17-phenyl-16(R,S)-fluoro-13,14-dehydro-PGE₂ ;

18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGE₂ ;

18,19,20-trinor-16(R,S)-fluoro-17-(4'-fluoro)-phenyl-13,14-dehydro-PGE.sub.2;

18,19,20-trinor-16(R,S)-fluoro-16-(3'-chloro)-phenyl-13,14-dehydro-PGE.sub.

EXAMPLE 6

A solution of 0.59 g of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGE₂ -11,15-bis-THP-etherin 80 ml of acetone is refluxed with 50 ml of an aqueous 0.25 N solutionof oxalic acid for 6 hours. The acetone is evaporated under vacuum andthe residue extracted repeatedly with ethyl ether. The combined etherextracts are washed with saturated aqueous ammonium sulfate and drieddown. The residue is chromatographed on acid-washed silica gel, elutedwith cyclohexane-ethyl acetate 80:20, yielding 300 mg of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGA₂.

Using the above procedure and starting with compounds prepared asoutlined in example 5, either in the form of the free alcohols or of the11,15-bis-THP-ethers or 11,15-bis-DIOX-ethers, one prepares thefollowing compounds:

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-PGA₂ ;

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGA₂ ;

13,14-dehydro-16(R,S)-fluoro-PGA₂ ;

13,14-dehydro-16S-methyl-16R-fluoro-PGA₂ ;

13,14-dehydro-16,16-difluoro-PGA₂ ;

13,14-dehydro-16(R,S)-fluoro-20-methyl-PGA₂ ;

13,14-dehydro-16S-fluoro-16R,20-dimethyl-PGA₂ ;

13,14-dehydro-16,16-difluoro-20-methyl-PGA₂ ;

13,14-dehydro-16(R,S)-fluoro-20-ethyl-PGA₂ ;

13,14-dehydro-16,16-difluoro-20-ethyl-PGA₂ ;

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-13,14-dehydro-PGA₂ ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGA₂ ;

18,19,20-trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGA₂ and its 16Risomer;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGA₂ ;

18,19,20-trinor-17-phenyl-16(R,S)-fluoro-13,14-dehydro-PGA₂ ;

18,19,20-trinor-17-phenyl-16,16-difluoro-13,14-dehydro-PGA₂.

EXAMPLE 7

To a solution of 0.58 g of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂α -11,15-bis-THP-etherin 12 ml of HMPA are added 44 mg of NaOH dissolved in 1 ml of water.This is stirred for 1 hour. Then add 150 mg of 1-bromo-propane andcontinue to stir for 12 hours. Then add 25 ml of water and extract withethyl ether. The combined organic phases are washed with saturatedaqueous ammonium sulfate, dried and evaporated to dryness to give 600 mgof 18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂α-11,15-bis-THP-ether-n-propylester.

By this procedure, starting with the 11,15-bis-acetalic ethers describedin examples 1, 2 and 3 and using instead of the 1-bromo-propane anotherhaloalkyl compound (for instance methyl iodide, ethyl iodide,bromo-butane, bromo-octane, bromo-decane) one can prepare the methyl,ethyl, butyl, octyl or decyl esters of the corresponding11,15-bis-acetalic ethers, that can then be deacetalated by theprocedure of example 3 to give the free hydroxy esters.

EXAMPLE 8

To a solution of 0.6 g of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂α-11,15-bis-THP-ether-n-propyl ester in 15 ml of anhydrous THF are added1.05 g of triphenyl phosphine and 0.79 g of p-phenylbenzoic acid. Thereaction mixture is maintained at 20°-22° C. and stirred while asolution of 0.7 g of ethyl azadicarboxylate in 6 ml of THF is added dropby drop over a five minute period. After an additional 10 minutes,evaporate to dryness and take up the residue in 75 ml of ethyl ether,wash with a saturated aqueous solution of bicarbonate, then water andevaporate to dryness. The residue is dissolved in 25 ml of acetone and18 ml of 0.2 N aqueous oxalic acid solution are added. The mixture isrefluxed for 30 minutes, concentrated under vacuum to remove theacetone, extracted with ethyl acetate and the organic phase isevaporated to dryness. The residue is chromatographed on silica gel,eluted first with cyclohexane-ethyl ether 6:4 and then with ethyl etherto give 0.5 g of 18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂β-9-p-phenylbenzoate-n-propylester. A solution of this compound in 10 mlof anhydrous propanol is treated with 140 mg of anhydrous potassiumcarbonate and the mixture is refluxed for an hour and 30 minutes. It isthen neutralized, the solvent is evaporated off and the reactionpartitioned between methylene chloride and water. The organic phase isdried and evaporated to dryness and the residue is chromatographed onsilica gel, first eluted with ethyl ether and then with ethylether-ethyl acetate 1:1. The yield is 340 mg of18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂β -n-propyl ester. Thiscompound is dissolved in a 8:2 mixture of methanol-water and 215 mg ofpotassium carbonate are added.

Reflux for one hour. After evaporation of the solvent, take up in water,acidify to pH 4.5 and extract with ethyl acetate. After evaporation ofthe organic phase, one obtains 280 mg of18,19,20-trinor-17-cyclohexyl-16-(R,S)-fluoro-PGF₂β. Using theprocedures of examples 7 and 8, starting with compounds prepared asdescribed in examples 1, 2 and 3, the following compounds are preparedas free acids or as alkyl esters:

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-PGF₂β ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-PFG₂β ;

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-PGF₂β ;

18,19,20-trinor-17-cyclohexyl-16,16-difluoro-PGF₂β ;

13,14-dehydro-16(R,S)-fluoro-PFG₂β ;

13,14-dehydro-16S-methyl-16R-fluoro-PGF₂β and its 16R-methyl-16S-fluoroisomer;

13,14-dehydro-16,16-difluoro-PGF₂β ;

13,14-dehydro-16(R,S)-fluoro-20-methyl-PGF₂β ;

13,14-dehydro-16S-fluoro-16R,20-dimethyl-PGF₂β and its16S-methyl-16R-fluoro-isomer;

13,14-dehydro-16,16-difluoro-20-methyl-PGF₂β ;

13,14-dehydro-16(R,S)-fluoro-20-ethyl-PGF₂β ;

13,14-dehydro-16,16-difluoro-20-ethyl-PGF₂β ;

18,19,20-trinor-17-cyclopentyl-16(R,S)-fluoro-13,14-dehydro-PGF₂β ;

18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGF₂β ;

18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-13,14-dehydro-PGF₂β ;

18,19,20-trinor-17-phenyl-16(R,S)-fluoro-13,14-dehydro-PGF₂β.

EXAMPLE 9

With humidity excluded, under an atmosphere of inert gas, and withconstant stirring, add drop by drop to a suspension of 410 mg of NaH(80% dispersion in mineral oil) in 100 ml of anhydrous benzene asolution of 3.82 g of dimethoxy-[2-oxo-3-fluoro-4-cyclohexyl]-butylphosphonate in 10 ml of anhydrous benzene. Stir for one hour and thenadd all at once a solution of 2 g of2-{[2β-formyl-3α,5α-dihydroxy-(3α-p-phenylbenzoate)]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone in anhydrous benzene. Stir for 15 minutes and thenadd 100 ml of a saturated aqueous solution of monobasic sodiumphosphate, separate the organic phase, wash it until neutral, dry andevaporate to dryness. The residue is chromatographed on silica gel andeluted with cyclohexane-ethylacetate 8:2 to give 2.1 g of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[3-keto-4-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone, m.p. 127°-129° C.

EXAMPLE 10

Add drop by drop to a suspension of 410 mg of NaH (80% dispersion inmineral oil) in 140 ml of anhydrous THF a solution of 3.82 g ofdimethyl-[2-oxo-3(R,S)-fluoro-cyclohexyl]-butyl-phosphonate in 10 ml ofTHF. Stir one hour until no more hydrogen evolves. Then add all at once2.432 g of N-bromo-succinimide. Stir for 15 minutes and then add asolution in THF of 2 g of2-{[2β-formyl-3α,5α-dihydroxy-(3α-p-phenylbenzoate)]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone. The mixture is stirred for one hour and then dilutedwith 200 ml of a 6% aqueous solution of monobasic sodium phosphate. Theorganic phase is separated, washed until neutral, dried and evaporatedto dryness. After chromatography on a silica gel column, 1.9 g areobtained of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ -lactone.

Following the procedures of examples 9 and 10, we obtained the followingacid-1,5-γ-lactones:2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[3-keto-4(R,S)-fluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[3-keto-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[3-keto-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[3-keto-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-trans-1-octenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4,4-difluoro-trans-1-octenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4S-methyl-4R-fluoro-trans-1-octenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone and its 4R-methyl-4S-fluoro isomer;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-trans-1-nonenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4S-fluoro-4R-methyl-trans-1-nonenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone and its 4S-methyl-4R-fluoro isomer;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4,4-difluoro-trans-1-nonenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-trans-1-decenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4,4-difluoro-trans-1-decenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone and the individual 4R and 4S isomers;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4,4-difluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-5-(4'-fluoro)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-5-(3'-chloro)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone;

2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[2-bromo-3-keto-4(R,S)-fluoro-5-(3'-trifluoromethyl)-phenyl-trans-1-pentenyl]-1.alpha.-cyclopentyl}-aceticacid-1,5-γ-lactone.

EXAMPLE 11

Dissolve 2.03 g of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[3-keto-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone in 120 ml of a 5:1 mixture of anhydrous ethylether:DME and add drop by drop, with stirring, 280 ml of a 0.07 Msolution of Zn(BH₄)₂ in ethyl ether, at room temperature. Stir for 30minutes and then add 40 ml of a saturated aqueous sodium chloridesolution and then 55 ml of 2N H₂ SO₄. Separate off the organic phase andwash to neutral, then dry and evaporate to dryness. The residue ischromatographed on a silica gel column eluted with methylenechloride-ether 9:1. One obtains 1.18 g of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone and 780 mg of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[(3R)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone, m.p. 116°-118° C., [α]_(D) =-105° (CHCl₃).

EXAMPLE 12

Dissolve 1.18 g of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone in 60 ml of anhydrous methanol. Add 360 mg ofanhydrous K₂ CO₃ and stir for 4 hours. Dilute with a saturated solutionof monobasic sodium phosphate and filter. The filtrate is concentratedto a small volume, taken up in water and extracted with ethyl acetate.The combined organic phases are washed to neutral, dried and evaporatedto dryness. The residue is chromatographed on silica gel, eluted with amixture of cyclohexane-ethyl acetate.

One obtains 750 mg of2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone.

EXAMPLE 13

Dissolve 370 mg of2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone in 50 ml of anhydrous benzene.

Add 2 mg of p-toluenesulfonic acid and 0.3 ml of 1,2-dihydropyran. Letstand at room temperature for 4 hours, then wash with 3% aqueouspotassium carbonate and with water until neutral. Dry and evaporate. Oneobtains 560 mg of2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone.

EXAMPLE 14

Dissolve 460 mg of2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone in 20 ml of anhydrous toluene. This solution iscooled to -70° C. and maintained at temperatures not higher than -60° C.while adding drop by drop a solution of 7.21% DlBA in toluene. After ithas all been added, stir for an additional 30 minutes. Then add 3.2 mlof 2 M isopropanol in anhydrous toluene, let the temperature rise to 0°C. and add 2 ml of water. Continue to stir for about 20 minutes and thenadd 500 mg of celite and 1.0 g of anhydrous sodium sulfate. Filter andevaporate the filtrate to give 400 mg of2-{3α,5α-dihydroxy-(3-THP-ether)-2β-[(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-1,5-γ-lactol.

Following the procedures of examples 11 to 13 and starting fromcompounds prepared according to the procedures of examples 9 and 10, oneobtains the following compounds (either as bis-THP-ethers or asbis-DlOX-ethers):2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactoland the individual 4S and 4R isomers;

2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-trans-1-octenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4S-methyl-4R-fluoro-trans-1-octenyl]-1α-cyclopentyl}-ethanal-γ-lactoland the 4S-fluoro-4R-methyl isomer;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-trans-1-octenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-trans-1-nonenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4S-fluoro-4R-methyl-trans-1-nonenyl]-1α-cyclopentyl}-ethanal-γ-lactoland the 4S-methyl-4R-fluoro isomer;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-trans-1-nonenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-trans-1-decenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-trans-1-decenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-5-cyclopentyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactoland the individual 4S and 4R isomers;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4,4-difluoro-5-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-(4'-fluoro)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-.gamma.-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-(3'-chloro)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-.gamma.-lactol;

2-{3α,5α-dihydroxy-2β-[2-bromo-(3S)-3-hydroxy-4(R,S)-fluoro-5-(3'-trifluoromethyl)-phenyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol.

These compounds can be deacetalated as shown in the following example(whether they are bis-THP-ethers or bis-DIOX-ethers).

EXAMPLE 15

0.5 g of2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-(3S)-3-hydroxy-(3-THP-ether)-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactolin 10 ml of acetone is treated with 5 ml of 0.25 N aqueous oxalic acidand refluxed for 90 minutes. The solvent is evaporated off under vacuumand the aqueous phase is extracted with ethyl acetate. The combinedorganic extracts are washed with saturated aqueous ammonium sulfate,dried and evaporated to dryness. The residue is chromatographed onsilica gel and eluted with ethyl acetate. to give 320 mg of2-{3α,5α-dihydroxy-2β-[(3S)-3-hydroxy-4(R,S)-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-γ-lactol.

EXAMPLE 16

0.78 g of2-{3α,5α-dihydroxy-(3α-p-phenylbenzoate)-2β-[(3R)-3-hydroxy-4S-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone in 25 ml of anhydrous methanol is reacted for twohours at room temperature with 150 mg of anhydrous K₂ CO₃.lt is thenneutralized and treated with amberlite 1R 120 resin (H⁺), filtered andthe filtrate evaporated to dryness. The residue is taken up in 10 ml ofdichloroethane and treated with 0.8 ml of 2,3-dihydropyran and 4 mg ofp-toluenesulfonic acid. After 2 hours at room temperature, add 0.3 ml ofpyridine and evaporate to dryness to give 0.9 g of2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3R)-3-hydroxy-(3-THP-ether)-4S-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-aceticacid-1,5-γ-lactone. This is dissolved in 10 ml of toluene, cooled to -60° C., and under an atmosphere of nitrogen is treated with 6.5 ml ofDIBA (0.5 M in toluene). After 30 minutes at -60° C., destroy the excessreagent with 7 ml of a 2 M solution of isopropanol in toluene, to obtain0.88 g of2-{3α,5α-dihydroxy-(3α-THP-ether)-2β-[(3R)-3-hydroxy-(3-THP-ether)-4S-fluoro-5-cyclohexyl-trans-1-pentenyl]-1α-cyclopentyl}-ethanal-1,5-γ-lactol.This compound is then reacted by the procedure outlined in example 1with the ylide generated from 0.92 g of NaH and 6.7 g oftriphenyl-(4-carboxy-butyl)-phosphonium bromide in 20 ml of DMSO, giving0.96 g of 18,19,20-trinor-17-cyclohexyl-16S-fluoro-15-epi-PGF₂α-11,15-bis-THP-ether. This compound is deacetalated in acetone withaqueous oxalic acid, as described in example 3, to give the18,19,20-trinor-17-cyclohexyl-16S-fluoro-15-epi-PGF₂α, [α]_(D) =+4.8°(EtOH).

In a parallel procedure, by oxidation of the11,15-bis-tetrahydropyranyl-ether derivative with Jones reagent,according to the procedure of example 5, followed by deacetalation, oneobtains 18,19,20-trinor-17-cyclohexyl-16S-fluoro-15-epi-PGE₂, [α]_(D)=-63.2°, [α]₃₆₅° =-326° (EtOH).

EXAMPLE 17

8 ml of 0.2 N oxalic acid are added to a solution of 380 mg of18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-13,14-dehydro-PGF₂.alpha.-11,15-bis-THP-ether, [α]_(D) =+9°, [α]₃₆₅° =+102° (acetone) in 10 ml ofacetone. After 12 hours at 38° C. the acetone is evaporated under vacuumand the residue is ectracted with ethyl ether. The organic extracts areevaporated to dryness and the residue chromatrgraphed on silica gel,eluted with 50:50 methylene chloride:ethyl acetate, to give 120 mg of18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-13,14-dehydro-PGF₂.alpha.,[α]_(D) =+38° (EtOH).

EXAMPLE 18

0.65 g of18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-13,14-dehydro-PGF₂.alpha.-11,15-bis-THP-ether is dissolved in 20 ml of acetone. The solution iscooled to -15° C. and 1.3 ml of Jones reagent are added. After 15minutes, dilute with 100 ml of benzene and wash until neutral with 20%ammonium sulfate solution. Dry over sodium sulfate and evaporate todryness to give 0.52 g of18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-13,14-dehydro-PGE₂-11,15-bis-THP-ether, [α]_(D) =-23° (acetone). This compound isdissolved in 15 ml of acetone, 12 ml of 0.1 N oxalic acid is added, andthe mixture allowed to stand for 12 hours at 37° C. The acetone isdistilled off under vacuum, the residue is extracted with ethyl acetateand the ethyl acetate extracts evaporated to dryness. The residue (0.39g) is chromatographed on 12 g of silica gel and eluted with methylenechloride-ethyl acetate (80:20) to obtain 0.2 g of18,19,20-trinor-17-cyclohexyl-16(S,R)-fluoro-13,14-dehydro-PGE₂, [α]_(D)=-6.2° (EtOH).

We claim:
 1. An optically active or racemic compound of the formula:##STR28## wherein: R is a member selected from the group consisting ofhydrogen, a C₁ -C₁₂ alkyl group and a cation of pharmaceuticallyacceptable base; the symbol represents a single or a double bond,wherein, when the symbol is a double bond, R₃ is a hydrogen atom and R₁and R₂ together form an oxo group, while, when the symbol is a singlebond, R₃ is hydroxy, and one of R₁ and R₂, is hydrogen and the other ishydroxy or `alkanoyloxy group containing up to 6 carbon atoms, abenzyloxy or a P-phenylbenzoyloxy group` or R₁ and R₂, taken together,form an oxo group;A is --C.tbd.C--; one of R₄ and R₅ is hydroxy and theother is hydrogen; R₆ is a member selected from the group consisting ofhydrogen, methyl and fluorine; n is zero, or an integer of 1 to 6; R₇ iscycloalkyl containing 3 to 7 ring carbon atoms.
 2. The compound of claim1 wherein R is methyl.
 3. The compound 18,19,20-trinor-17-cyclohexyl13,14-dehydro-16(S,R)-fluoro-PGF₂α, the lower alkyl esters or thepharmaceutically acceptable salts thereof.
 4. The compound18,19,20-trinor-17-cyclohexyl-16R-fluoro-13,14-dehydro-PGF₂α, the methylester or the pharmaceutically acceptable salts thereof.
 5. The compound18,19,20-trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGF₂α, the methylester or the pharmaceutically acceptable salts thereof.
 6. A compoundselected from the group consistingof:18,19,20-trinor-17-cyclohexyl-16(R,S)-fluoro-13,14-dehydro-PGF₂α18,19,20-trinor-17-cyclohexyl-16R-fluoro-13,14-dehydro-PGF₂α,18,19,20-trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGF₂α,18,19,20-trinor-17-cyclohexyl-16,16-di-fluoro-13,14-dehydro-PGF₂.alpha.,a 16-fluoro-18,19,20-trinor-17-cyclopentyl-13,14-dehydro-PGF₂α, a16-fluoro-18,19,20-trinor-17-cyclopentyl-13,14-dehydro-PGE₂, a16-fluoro-18,19,20-trinor-17-cyclohexyl-13,14-dehydro-PGE₂,18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGF₂.alpha.,18,19,20-trinor-17-cyclopentyl-16,16-difluoro-13,14-dehydro-PGE₂,18,19,20-trinor-17-cyclohexyl-16,16-difluoro-13,14-dehydro-PGE₂, and thelower alkyl esters and the pharmaceutically acceptable salts thereof. 7.The compound of claim 6 wherein the lower alkyl ester is the methylester.
 8. A luteolytic, abortive or antiulcer pharmaceutical compositioncomprising an effective amount of a compound of claim 1 together with apharmaceutically acceptable carrier or diluent.
 9. A method of inducingabortion in a subject in need of said treatment, said method comprisingadministering to said subject an abortion-inducing amount of a compoundof claim 1 wherein R₂ and R₃ are both hydroxy, or wherein R₃ is hydroxyand R₁ and R₂ together form an oxo group.
 10. The method of claim 9,wherein said compound is18,19,20-trinor-17-cyclohexyl-13,14-dehydro-16(S,R)-fluoro-PGF₂.alpha.,the lower alkyl esters or the pharmaceutically acceptable salts thereof.11. A method of inducing abortion in a subject comprising administeringto said subject an abortion-inducing amount of18,19,20-trinor-17-cyclohexyl-16R-fluoro-13,14-dehydro-PGF₂α, the methylester or the pharmaceutically acceptable salts thereof.
 12. A method ofinducing abortion in a subject comprising administering to said subjectan abortion-inducing amount of18,19,20-trinor-17-cyclohexyl-16S-fluoro-13,14-dehydro-PGF₂α, the methylester or the pharmaceutically acceptable salts thereof.
 13. A method oftreating ulcers in a subject in need of said treatment, said methodcomprising administering to said subject an effective amount of acompound of claim 1, wherein R₃ is hydroxy and R₁ and R₂ together forman oxo group.